Significance: Apoptosis is central to the pathogenesis of emphysema, and is widespread in acute lung injury, sepsis, and viral pneumonias. Apoptotic cells (AC) must be cleared efficiently to limit lung inflammation and to maintain immunologic tolerance. When lung infections are handled successfully, leukocytes die by apoptosis and their clearance by alveolar macrophages (AMO) hastens lung repair via secretion of TGF-beta, PGE2 and IL-10, immunosuppressive mediators that can also compromise defenses against pathogens and promote fibrosis. Thus, understanding the mechanisms and consequences of the AMO response to AC, the Long-Term Goals of this project, could impact many areas of pulmonary medicine. This project has studied a receptor tyrosine kinase called MerTK, which is essential for MO uptake of AC. Novel preliminary data are presented showing that exposure to AC induces MerTK to interact with two MO molecules previously implicated in AC uptake, the type A scavenger receptor (SR-A) and the lipoprotein receptor-related protein (LRP). Association with SR-A precedes MerTK activation, whereas association with LRP is followed by specific serine phosphorylation essential for LRP signaling. Blocking MerTK ablates AC- induced activation of ERK, which is required for alpha chemokine induction. This proposal will test the hypothesis that MerTK interacts sequentially with SR-A, LRP and specific intracellular molecules to induce MO to recognize, ingest and produce chemokines in response to AC. Experiments will analyze the AMO cell line MH-S and resident AMO from normal mice, or from gene-targeted mice lacking SR-A, or lacking LRP specifically on the MO lineage. Techniques will include assays of phagocytosis and adhesion;immunoprecipitation and Western analysis;real-time PCR;confocal microscopy;transient transfections;and gene silencing using lentiviral infection with small interfering RNAs. Relevance: Death of lung cells is a feature of emphysema, some pneumonias, and other lung injuries. These dead cells must be cleared correctly to prevent worsened lung injury, scarring, or immune compromise. This project studies a molecule called MerTK that appears to control clearance. Understanding MerTK could lead to new treatments to prevent complications of many types of lung damage.